1. Field of the Invention
The present invention relates to a technique for a magnetic signal measuring apparatus and a magnetic signal measuring method which measure a magnetic signal derived from a magnetic substance binding to a substance to be measured (for convenience, hereinafter referred to as a measured substance) in a liquid.
2. Description of the Related Art
In recent years, a technique for an immunological test has made rapid progress in diagnosis of infection, cancer, allergy and the like. The immunological test is a technique of detecting and quantifying a measured substance in a biological body based on a specific binding reaction between an antigen and an antibody. The measured substance in the immunological test is mainly a protein and is specifically a pathogenic microorganism, an antigen derived from foods, an immunoglobulin, a hormone, a tumor marker or the like. In the immunological test, one or several types of antibodies whose binding-capacity to a measured substance is preliminarily known are used to detect the measured substance in the biological body based on the presence or absence of binding between the measured substance and the antibodies and/or the degree of binding therebetween.
Conventionally, an optical immunological test is used in which an antibody whose binding capacity to a measured substance is known is labeled with a luminescent substance, a fluorescent substance, enzyme or the like and the degree of binding between the antibody and the measured substance is optically detected. The antibody labeled in the method of such an optical immunological test is referred to as a labeled antibody. For example, an FTA (Fluorescent Treponemal Antibody test), an EIA (Enzyme ImmunoAssay) and the like are known as representative methods.
Herein, inmost of optical immunological tests, when labeled antibodies which have not bound to measured substances remain, a non-specific signal is detected from a luminescent substance or a fluorescent substance. To cope with this, a process of flushing and removing redundant labeled antibodies is required.
On the other hand, unlike the optical immunological test, a technique is known as a magnetic immunological test, which detects a measured substance using a magnetic method such as described in Patent Document 1 (Japanese Patent No. 4676361) and Patent Document 2 (Japanese Patent No. 5189825). In the magnetic immunological test, an antibody is first labeled with a magnetic particle. Thus, the magnetic particle labeled by the antibody is referred to as a magnetic particle antibody. Then, a magnetic signal due to a binding reaction between the measured substance and the magnetic particle antibody is detected by a magnetic sensor.
For example, in a case of using a SQUID (Superconducting QUantum Interference Device) magnetic sensor, a sample is produced in which measured substances fixed onto a bead carrier having a particle diameter of micron scale and magnetic particle antibodies are bound to each other in a solution. Then, an external direct-current (DC) magnetic field is applied to the sample to magnetize the magnetic particle antibodies. Next, when the external DC magnetic field is shut off, the magnetic particle antibody which has bound to the measured substance more increases in size than the magnetic particle antibody which has not bound to the measured substance and accordingly a rotational Brownian motion of the former magnetic particle antibody becomes slow. This causes the magnetic particle antibody binding to the measured substance to have remanent magnetism, thereby allowing a magnetic signal derived from the magnetic particle antibody to be detected.
On the other hand, the magnetic particle antibody not having bound to the measured substance also exists in the solution. The magnetic particle antibody not having bound to the measured substance has a smaller particle diameter because it exists alone, and thus a rotational Brownian motion thereof becomes rapid. Accordingly, as for the magnetic particle antibody not binding to the measured substance, the direction of the magnetic moment thereof easily becomes random and thus there is no remanent magnetism therein. This makes the magnetic particle antibody not binding to the measured substance unable to be detected as a magnetic signal.
Thus, the magnetic immunological test has an advantage in that it requires no process of flushing and removing magnetic particle antibodies, because it utilizes the difference of remanent magnetic property of the magnetic particle antibodies, which is influenced by the presence or absence of binding to the measured substance.
The magnetic immunological test as described above requires a process of preliminarily magnetizing magnetic particle antibodies, prior to measuring a magnetic signal. The intensity of a magnetic signal detected from the magnetic particle antibody depends on the intensity of an externally-applied magnetic field and the density of the magnetic moments of the magnetic particle antibodies. Accordingly, in the magnetic immunological test, the more intense the magnetic field becomes and the higher the density of the magnetic moments becomes, the higher the intensity of a magnetic signal to be measured becomes. As an example of application of this principle, there is a method such as described in Patent Document 3 (Japanese Patent Application Publication No. 2004-061144), in which, after an antigen-antibody reaction process, a sample is dried with a magnetic field of 0.5 to 500 gauss being applied. In this method, drying the sample in the magnetic field makes it possible to align the directions of the magnetic moments in the magnetic particle antibodies with each other and to increase the density of the magnetic moments. Thus, according to the method described in Patent Document 3, an intense magnetic signal can be obtained.
However, the method described in Patent Document 3 requires a process of preliminarily flushing and removing redundant magnetic particle antibodies not binding to measured substances. This is because, when redundant magnetic particle antibodies remain in drying the sample in the magnetic field, a blank value increases. The blank value means a value of a magnetic signal detected even where the abundance of the measured substances is “0”. Also, in general, since an immunological test requires a short-time and efficient test, a drying process requiring a long time, such as encountered in the method described in Patent Document 3, is not suitable for such an immunological test.
On the other hand, the methods described in Patent Document 1 and Patent Document 2 use a liquid sample thereby enabling a short-time test, as compared to the method described in Patent Document 3 in which the sample is dried. However, in the process of preliminarily applying an external DC magnetic field to the sample to magnetize the magnetic particle antibodies, a phenomenon is caused in some cases in which redundant magnetic particle antibodies not binding to measured substances flocculate non-specifically. This is because the externally-applied magnetic field is intensified for the purpose of intensifying remanent magnetism in the magnetic particle antibodies to obtain an intense magnetic signal. Thus, when non-specific flocculation of the magnetic particle antibodies is caused, a clump of magnetic particle antibodies is produced in which the directions of magnetic moments in the magnetic particle antibodies are aligned with each other and the density of the magnetic moments is also increased. Consequently, a problem occurs in that a magnetic signal is generated from such a clump of magnetic particle antibodies to increase a blank value.